Gene Therapy Lesson: Definition & Key Concepts
Lesson Overview
- What Is Gene Therapy?
- Applications of Gene Therapy
- Key Historical Milestones
- Viral Vectors Used in Gene Therapy
- Suicide Gene Therapy and HSV-TK
- Famous Case: SCID and Leukemia-Like Condition
- Insertional Mutagenesis vs. Non-Integrating Vectors
- Gene Therapy Risks
- Notable Gene Therapy Incidents
- Successful Gene Therapies
- Replication-Deficient Vectors and Gene Products
- In Vivo vs. Ex Vivo Gene Therapy
- Somatic vs. Germline Gene Therapy
Gene therapy is a modern biomedical technique used to treat or prevent diseases by modifying genes within a person's cells. It works by correcting defective genes responsible for disease development.
While originally developed in the early 1970s, gene therapy gained significant attention in the 1990s with the first successful human trials. Today, it plays a critical role in addressing genetic disorders, certain cancers, and rare diseases.
What Is Gene Therapy?
Gene therapy involves altering the genetic material of a patient's cells to produce a therapeutic effect.
- A healthy gene is introduced into cells to replace or supplement a defective one.
- It aims to correct genetic disorders at their root cause.
- It is usually applied to somatic cells, not reproductive (germline) cells.
- It is not related to reproduction, sexual or asexual, since no new organism is created.
Applications of Gene Therapy
Gene therapy is primarily used to treat serious diseases that are otherwise incurable or hard to manage.
- Genetic disorders like Severe Combined Immunodeficiency (SCID)
- Certain types of cancers
- Blood disorders such as beta-thalassemia
- Rare neurological diseases like spinal muscular atrophy (SMA)
These therapies are most effective for conditions caused by a single faulty gene.
Key Historical Milestones
Gene therapy has a rich history marked by breakthroughs and challenges.
| Year | Event | Description |
| 1972 | Concept Proposed | Initial idea for gene therapy introduced |
| 1990 | First Treatment | SCID treated using retroviral gene therapy |
| 1999 | Major Setback | A patient died due to an immune reaction to adenovirus |
| 2003+ | Clinical Advances | Therapies for blindness, SMA, and cancer emerged |
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Viral Vectors Used in Gene Therapy
Gene delivery often uses modified viruses, called vectors, to transport therapeutic genes into cells.
Common Viral Vectors
| Vector Type | Integration into Genome | Main Use Cases | Risk Factors |
| Adenovirus | No | Cancer, vaccines | Immune reactions, toxicity |
| Retrovirus | Yes | SCID, leukemia | Insertional mutagenesis |
| Lentivirus | Yes | Blood disorders, HIV-related trials | Long-term expression, integration |
| AAV (Adeno-associated virus) | No | Neurological diseases, SMA | Low toxicity, long expression |
Suicide Gene Therapy and HSV-TK
Suicide gene therapy uses genes that kill cells when activated by a drug.
- A common gene used is HSV-TK (Herpes Simplex Virus Thymidine Kinase).
- When HSV-TK is inserted into cancer cells and exposed to ganciclovir, it converts the drug into a toxic substance.
- This selectively kills the cancer cells while sparing healthy tissue.
Pseudotyping in Gene Therapy
Pseudotyping is a method used to alter the tropism (cell targeting ability) of viral vectors.
- The envelope protein of a virus is replaced with one from another virus.
- A popular envelope protein used is VSV-G.
- This expands the virus's ability to infect a wider range of human cells.
- Pseudotyped viruses are commonly used in lentiviral gene therapy.
Famous Case: SCID and Leukemia-Like Condition
A notable incident involved a young boy treated for SCID using a retroviral vector.
- The retrovirus inserted near a proto-oncogene promoter.
- This led to uncontrolled cell growth, similar to leukemia.
- It highlighted the risk of insertional mutagenesis in integrating vectors like retroviruses.
Insertional Mutagenesis vs. Non-Integrating Vectors
Insertional mutagenesis is when a gene inserts itself into the genome and disrupts normal genes.
- Retroviruses and lentiviruses can cause this due to their integrating nature.
- Adenoviruses do not integrate into the genome, so insertional mutagenesis is not a concern.
| Vector Type | Integration | Risk of Insertional Mutagenesis |
| Retrovirus | Yes | High |
| Lentivirus | Yes | Moderate |
| Adenovirus | No | None |
| AAV | No | None |
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Gene Therapy Risks
While promising, gene therapy is not without risks.
Common Risks
- Immune Reaction: High doses of adenoviruses can trigger severe immune responses.
- Toxicity: The viral dose itself may cause damage to organs.
- Insertional Mutagenesis: Can occur if integrating vectors activate oncogenes.
- Uncontrolled Gene Expression: Overexpression may lead to abnormal cell function.
Notable Gene Therapy Incidents
Jesse Gelsinger Case
- Treated for Ornithine Transcarbamylase deficiency in 1999.
- Died due to a severe immune reaction to the adenovirus vector.
- Brought global attention to gene therapy safety.
Successful Gene Therapies
Gene therapy has achieved success in treating some previously incurable conditions.
Examples of Success
| Disease | Therapy Type | Outcome |
| SCID (ADA deficiency) | Ex vivo retrovirus | Improved immune function |
| Spinal Muscular Atrophy | AAV-based | Motor function recovery in infants |
| Retinal Dystrophy (RPE65) | AAV-based | Vision improvement |
| Beta-thalassemia | Lentiviral vector | Reduced need for transfusions |
Replication-Deficient Vectors and Gene Products
Some gene therapies use replication-deficient adenoviruses to carry the p53 gene.
- p53 is a tumor-suppressor gene commonly mutated in cancers.
- These vectors deliver functional p53 to trigger cancer cell death.
- Product names include Gendicine, Advexin, and SCH58500.
- Oncorine is not a p53 gene product but rather an oncolytic virus.
In Vivo vs. Ex Vivo Gene Therapy
Two main approaches are used depending on the condition and target cells.
| Approach | Process Description | Examples |
| Ex Vivo | Cells are removed, modified, and reintroduced | Bone marrow therapy for SCID |
| In Vivo | Vectors are directly injected into the body | SMA therapy via intravenous AAV |
Somatic vs. Germline Gene Therapy
- Somatic Therapy affects only the treated individual.
- Germline Therapy affects reproductive cells and is not used clinically due to ethical concerns.
- All current approved gene therapies are somatic.
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